Discovery of biphenyl-substituted diarylpyrimidines as non-nucleoside reverse transcriptase inhibitors with high potency against wild-type and mutant HIV-1

作者：Jin, KaiJun; Yin, Hong; De Clercq, Erik; Pannecouque, Christophe; Meng, Ge; Chen, FenEr^*

来源：European Journal of Medicinal Chemistry, 2018, 145: 726-734.

DOI：10.1016/j.ejmech.2018.01.016

• Biphenyl
• Diarylpyrimidines
• HIV-1
• Reverse transcriptase
• Dock
• SAR

A novel series of diarylpyrimidine (DAPY) derivatives bearing the biphenyl motif with multiple substituted groups was synthesized as human immunodeficiency virus (HIV)-1 non-nucleoside reverse transcriptase inhibitors. All of the target compounds were evaluated for their in vitro activity against HIV in MT-4 cells. Most of the compounds exhibited excellent activity with low nanomolar EC50 values against wild-type, single and double mutant HIV-1 strains. Compound 4b displayed an EC50 value of I nM against HIV-1 IIIB, 1.3 nM against L100I, 0.84 nM against K103 N, 1.5 nM against Y181C, 11 nM against Y188L, 2 nM against E138K, 10 nM against K103 N + Y181C, and almost 110 nM against F227L + V106. The improvement in the selectivity and potency of the target molecules against the wild type and mutant HIV-1 strains validated our hypothesis. The biphenyl ring in the DAPY derivatives could strengthen the pi-pi stacking effect between the target molecule and the non-nucleoside inhibitor binding pocket in the reverse transcriptase by extending the conjugating systems. This research represented a significant step toward the discovery of novel therapeutic DAPYs for treating acquired immunodeficiency syndrome in patients infected with HIV-1.

• 出版日期2018-2-10
• 单位复旦大学; 河北医科大学